Carotid bodies are the sensory organs for monitoring changes in arterial blood O2. Chronic perturbations in environmental O2 profoundly influence the hypoxic sensing ability of the carotid body. Intermittent hypoxia (IH) represents one such chronic perturbation of O2 levels in arterial blood. Adult and neonatal mammals experience IH as a consequence of recurrent apneas. This presentation will focus on the impact of IH on hypoxic sensing by the carotid body and its consequences on cardio-respiratory systems. Exposing adult and neonatal rats to chronic IH leads to sensitization of the carotid body response to acute hypoxia and this response is mediated by reactive oxygen species (ROS)-dependent recruitment of endothelins (Pawar et al. 2009). In addition, chronic IH induced sensory long-term facilitation (sLTF) in adult rodents via 5-HT-dependent NADPH oxidase-2 activation (Peng et al. 2009). IH-evoked changes in the carotid body are associated with increased number of apneas, activation of sympathetic activity and elevated blood pressures. Analysis of the molecular mechanisms revealed that HIF family of transcriptional activators play critical roles in IH-evoked alterations in carotid body function (Nanduri et al. 2008). IH increased HIF-1α protein via Ca2+-dependent activation of mTOR and prolyl hydroxylases (Yuan et al. 2008); whereas down-regulated HIF-2α by Ca2+-activated proteases (calpains) (Nanduri et al. 2009). Up-regulation of HIF-1 appears to contribute to increased pro-oxidants; whereas HIF-2α down-regulation was associated with decreased transcription of anti-oxidant enzyme (Nanduri et al. 2009). The differential regulation of HIF-1 and HIF-2 by IH lead to oxidative stress which by way of recruiting transmitters contribute to plasticity of acute O2 sensing by the carotid body. Supported by grants from NIH-HL- 090554; HL-086493.